12-132685415-C-T

Variant names:

• chr12-132685415-C-T
• rs11147005
• NM_006231.4:c.62+1839G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006231.4(POLE):​c.62+1839G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 152,172 control chromosomes in the GnomAD database, including 32,156 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.64 (32156 hom., cov: 34)
• Consequence: POLE NM_006231.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.71
• Publications: 12 publications found

Genes affected

POLE (HGNC:9177): (DNA polymerase epsilon, catalytic subunit) This gene encodes the catalytic subunit of DNA polymerase epsilon. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in this gene have been associated with colorectal cancer 12 and facial dysmorphism, immunodeficiency, livedo, and short stature. [provided by RefSeq, Sep 2013]

POLE Gene-Disease associations (from GenCC):

• POLE-related polyposis and colorectal cancer syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• colorectal cancer, susceptibility to, 12

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• facial dysmorphism-immunodeficiency-livedo-short stature syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

  Inheritance: AR Classification: STRONG Submitted by: G2P
• IMAGe syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Polymerase proofreading-related adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.06).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006231.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	NM_006231.4	MANE Select	c.62+1839G>A		intron	N/A	NP_006222.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	ENST00000320574.10	TSL:1 MANE Select	c.62+1839G>A		intron	N/A	ENSP00000322570.5
	POLE	ENST00000535270.5	TSL:1	c.62+1839G>A		intron	N/A	ENSP00000445753.1
	POLE	ENST00000537064.5	TSL:1	n.62+1839G>A		intron	N/A	ENSP00000442578.1

Frequencies

GnomAD3 genomes AF: 0.644 AC: 97921 AN: 152054 Hom.: 32115 Cov.: 34

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.585

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.601

Gnomad MID AF: 0.656

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.654

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.644 AC: 98009 AN: 152172 Hom.: 32156 Cov.: 34 AF XY: 0.636 AC XY: 47312 AN XY: 74398

African (AFR) AF: 0.618 AC: 25640 AN: 41514

American (AMR) AF: 0.584 AC: 8930 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.779 AC: 2702 AN: 3470

East Asian (EAS) AF: 0.307 AC: 1590 AN: 5180

South Asian (SAS) AF: 0.602 AC: 2906 AN: 4824

European-Finnish (FIN) AF: 0.601 AC: 6363 AN: 10586

Middle Eastern (MID) AF: 0.661 AC: 193 AN: 292

European-Non Finnish (NFE) AF: 0.700 AC: 47610 AN: 68002

Other (OTH) AF: 0.652 AC: 1375 AN: 2110

Alfa AF: 0.676 Hom.: 18233

Bravo AF: 0.640

Asia WGS AF: 0.517 AC: 1803 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	1.2
DANN	Benign	0.56
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11147005; hg19: chr12-133262001; COSMIC: COSV57691628; COSMIC: COSV57691628;